Full text of DOI:10.1592/phco.21.11.940.34520

P RA C TIC E I N S IG H TS
Discontinuation of Antihypertensive Drugs Due to
Adverse Events: A Systematic Review and Meta-analysis
Susan D. Ross, M.D., Kasem S. Akhras, Pharm.D., Shuhuan Zhang, M.S.,
Michael Rozinsky, B.A., and Luba Nalysnyk, M.D., M.P.H.
We conducted a systematic review of randomized, controlled, monotherapy
trials since 1990 of oral antihypertensive agents in patients with essential
hypertension. Our objective was to quantify the frequency of discontinuation
of antihypertensive agents due to adverse events from a meta-analysis of the
studies. A total of 190 studies met inclusion criteria. The highest frequency
of discontinuations due to adverse events (DAEs) occurred with calcium
channel blockers (6.7%) and ␣-adrenergic blockers (6.0%); the lowest with
diuretics and angiotensin receptor blockers (each 3.1%). Only in calcium
channel blocker studies was the frequency of DAEs greater in treated patients
than in patients receiving placebo, but the difference was not significant. This
systematic review suggests that the frequency of DAEs in monotherapy
antihypertensive trials varies across drug classes and should be considered
when choosing drugs for patients with essential hypertension.
(Pharmacotherapy 2001;21(8):940–953)
When choosing antihypertensive agents for
patients with essential hypertension, practi-
tioners are well advised to follow current
evidence-based guidelines.1, 2 These recom-
mendations are driven primarily by evidence of
efficacy and safety. Little is known about the
likelihood of drug discontinuation, yet these
considerations should factor into treatment
decisions regarding patients with long-term
conditions such as essential hypertension.
The primary objective of our analysis,
therefore, was to quantify the frequency of
discontinuations due to adverse events (DAEs)
according to the class of antihypertensive agent:
␤-blockers, calcium channel blockers,
angiotensin receptor blockers, angiotensin-
converting enzyme inhibitors (ACEs), ␣-
adrenergic blockers, and diuretics. Secondary
objectives were to assess timing (early vs late) of
DAEs and frequency of adverse events (AEs) by
major organ system and class of drug. To achieve
these objectives, we performed a systematic
review of the literature to build the evidence base
and then performed quantitative data syntheses
using meta-analytic methods where appropriate.
Since the taxonomy of drug safety suffers from
significant nonuniformity, we used a broad
definition of adverse drug event: any noxious,
unintended effect occurring at doses admin-
istered to humans for therapy that is not
attributable to therapeutic failure or drug abuse.
The term adverse event includes noncompliance
and errors of administration, as distinct from
adverse drug reaction, which does not. We
believe this definition of adverse event
encompassed most, if not all, DAEs described in
the articles that we reviewed. However, in most
cases the meaning of the adverse event term was
implicit, not explicit.
From MetaWorks Inc., Medford, Massachusetts (Drs.
Ross and Nalysnyk, Mr. Zhang, and Mr. Rozinsky) and
Pharmacia Corporation, Skokie, Illinois (Dr. Akhras).
Funded in part by Pharmacia Corporation.
Address reprint requests to Susan D. Ross, M.D.,
MetaWorks Inc., 10 President’s Landing, Medford, MA
02155; e-mail: SDR@metawork.com.
Methods
In general, procedures for our review followed

DISCONTINUATION OF ANTIHYPERTENSIVE DRUGS DUE TO ADVERSE EVENTS Ross et al 941
established best methods for the evolving science
of systematic review research.3, 4 A protocol was
written, prospectively, which stated the
objectives, search criteria, study selection criteria,
data elements of interest, and plans for analysis.
reviewed. Whether discontinuations were
initiated by patients or physicians typically was
not noted. Timing of DAEs was sought both as a
categorical variable (early [≤ 1 mo] vs late [> 1
mo]), and as a continuous variable (actual time
patient received study drug, if reported). When
several AEs led to discontinuation of a patient
from a study, only the most severe event (as
determined by a physician) was captured, or if
events appeared comparable in terms of severity,
the first listed was captured. For example, if a
patient had palpitations, angina, and myocardial
infarction, the DAE was captured as myocardial
infarction.
Each accepted randomized, controlled trial was
appraised using a Jadad quality score5 for features
of randomization method used (0–2 points
possible), blinding of treatment (0–2 points
possible), and accounting for all patients entered
and withdrawn (0–1 point possible).
Literature Search
We sought randomized, controlled trials of
antihypertensive agents in adults with essential
hypertension. The trials were to have parallel-
group designs and be at least 1 week long. The
the number of patients/group with DAEs had to
be reported. We first searched MEDLINE from
1990 to November 1, 1999, using the following
terms: blood pressure, hypertension, anti-
hypertensive agent, trial, human, and English. In
the same manner, we searched Current Contents
CD-ROM and Cochrane Library. We manually
searched bibliographies of accepted studies for
additional potentially eligible citations.
To be eligible for inclusion in our review,
studies had to enroll at least 10 patients with
essential hypertension who were otherwise well.
We did accept studies that selected for
hypertensive patients who might also have
diabetes mellitus or left ventricular hypertrophy
(LVH) since these are common comorbid
conditions. Conversely, studies that selected for
patients with any other complicating illness (e.g.,
congestive heart failure or renal failure) were not
accepted. Other exclusion criteria included
postoperative studies, cardiac ischemia studies,
studies of patients with isolated systolic
hypertension, and studies reporting subgroup
results from larger studies. Also excluded were
hemodynamic physiology studies and
pharmacokinetic or pharmacodynamic studies.
Furthermore, since our objective was to associate
the occurrence of discontinuations with
particular study drugs, combination drug trials
were excluded. Last, studies using within-group
dose titrations were acceptable; however, studies
were excluded if all groups received the same
drug but different dosages, schedules, or
formulations.
Statistics
The primary outcome of interest was frequency
of DAEs in treatment and placebo groups.
Although timing of DAEs was sought, actual
duration of exposure to the drug before DAE
occurred was reported too infrequently to be
directly analyzed as either a categorical or a
continuous variable. Although we recognize that
study duration cannot be readily substituted as a
surrogate for duration of exposure at the time of
DAE (since DAE on a long-term study could have
occurred early or late), we calculated frequency
of DAEs in short- and long-term studies to see if
any major discrepancies occurred in overall event
rates.
Secondarily, frequency of patients with any AE
was computed according to drug class and major
organ system. For frequency of both DAEs and
AEs in treatment groups, the numerator was the
number of patients with the event and the
denominator the number of patients analyzed for
safety in each group. If the number analyzed for
safety was not reported, the randomized number
was used. Treatment group frequencies were
pooled across studies and grouped by category of
antihypertensive agent. For calcium channel
blockers, since their AE profiles differ, two
subclasses were analyzed: nondihydropyridines
(diltiazem and verapamil formulations) and
dihydropyridines (nifedipine, amlodipine,
felodipine, and nisoldipine).
Database Development
Data from all accepted studies were extracted
to a data form by one investigator and were
consensed by a second investigator before data
entry. From each study, data on patient,
treatment, and study characteristics; and
numbers of patients with DAEs and AEs, overall
and broken down by major organ system, were
In a regression model we studied the potential
influence of study variables such as location

942
PHARMACOTHERAPY Volume 21, Number 8, 2001
(North America, Europe, both, or other),
publication years (before 1995, or 1995 or later),
and quality score (< 3 or ≥ 3), and of group
variables such as gender distribution, mean age
(< 50 vs ≥ 50 yrs), concurrent diabetes mellitus,
and baseline LVH by electrocardiography [ECG]
or echocardiography [ECHO] on the frequency
of DAEs.
Within-study treatment group differences in
the frequency of DAEs were meta-analyzed in
studies that contained similar drug-class
comparisons (e.g., studies comparing ␤-blockers
with calcium channel blockers). The outcomes
from many studies were combined in meta-
analyses using both fixed effects models (FEMs)6
and random effects models (REMs).7, 8 Outcomes
were expressed as risk differences with 95%
confidence intervals (CIs). An FEM assumes that
studies are homogeneous with the same
underlying distribution of mean and variance,
whereas REM assumes heterogeneity of studies.
Typically, differences between FEMs and REMs
are small; REMs provide the more conservative
estimate. The REM results are reported below.
All calculations were performed using SAS
software version 6.12 (SAS, Cary, NC).
average study duration is narrow, extending from
12.0 weeks in angiotensin receptor blocker
groups to 19.8 weeks for diuretic groups.
Placebo groups appear to have the shortest
average duration, 8.9 weeks.
The average Jadad quality score was 3.2 (range
1–5); 80% of studies scored 3 or higher. This
suggests that the studies were mostly medium to
high quality. Given the study designs that we
were seeking, it is important to note that all
studies received at least one point for
randomization but not necessarily full credit for
reporting withdrawals. A study might report
DAEs but not account for all patients enrolled,
and therefore might not receive points for
describing all withdrawals fully.
Patient and Treatment Characteristics
Patient and treatment characteristics are
summarized in Table 1. Overall, 409 treatment
groups comprised 28,922 patients. Most
frequently studied were calcium channel
blockers, followed closely by ACE inhibitors; ␣-
adrenergic blockers had the least coverage in the
database. In studies reporting patients with
diabetes mellitus, few patients had the disease.
Similarly, in the few studies reporting LVH at
baseline, less than a third of patients had the
condition.
Results
Studies
Most patients in all studies were middle-aged
men, and little difference was apparent in the
makeup of patients when stratified by drug class
categories, except that the proportion of patients
who previously had received antihypertensive
drugs was somewhat higher in ␣-adrenergic
blocker groups than in other monotherapy drug
groups.
The literature search yielded 4057 citations,
most of which were rejected immediately for
reasons such as language, study design, and
patient population. Full papers were retrieved
for 529 abstracts that had no apparent reason for
exclusion. Of these, 339 were subsequently
rejected because DAEs were not reported, add-on
drugs were present, or DAEs were not extractable
by treatment group. Therefore, 190 studies
satisfied all inclusion criteria and were accepted
for review and meta-analysis; these studies are
listed in the Appendix.
All eligible trials were randomized, parallel-
group study designs, as required by the project
protocol. Accepted trials were conducted in
Europe (99 studies), North America (57 studies),
or both Europe and North America or other
locations (34 studies). A total of 120 studies
noted some form of industry sponsorship. Study
duration ranged from 1.4 weeks–2 years; 22
studies lasted 1 month or less, and 4 continued
for longer than 1 year. Intended time for
receiving study drug was used as the study
duration. Therefore, duration does not include
washout or placebo run-in periods. The range of
Outcomes
In interpreting the results that follow, it should
be noted that AE tallies did not always represent
all events under study but only those occurring
in a certain percentage of patients. The
thresholds for reporting AEs were variable with,
for example, only AEs in at least two patients, or
at least 3%, 5%, or 15% frequency reported.
Also, some authors reported all events, but others
reported only those events judged possibly or
probably related to study drug. Since the
strength of relationship of AE to study drug (i.e.,
definite, probable, possible, or unlikely) was
often not reported, the only causal relationship
that can be assessed with confidence is the
discontinuation event as definitely related to the

DISCONTINUATION OF ANTIHYPERTENSIVE DRUGS DUE TO ADVERSE EVENTS Ross et al 943
Table 1. Patient Characteristics by Treatment Group
Type of Antihypertensive Drug
Calcium Channel Blocker
Characteristic
Patients randomized (%)
No. analyzed
Overall Diuretic
BB
16.5
ACE
23.2
6727
Total
DHP Non-DHP ARB
25.9 6.1 10.4
1772 2997
AAB Placebo
3.9 7.7
1120 2220
100
28,922
409a
6.3
1814
29
32
9264
119a
4780
7492
No. of tx arms
68a
108
97a
22
30
14
41
Patients analyzed for
safety (no.)
No. tx arms
28,708
410a
1799
29
4676
67a
6674
108
9253
121a
7490
99a
1763
22
2994
30
1103
14
2209
41
Mean age (yrs)
No. of tx arms
54.3
355
55.6
25
53.3
62
54.2
86
54.4
108
54.4
90
54.1
18
56.3
28
50.2
7
54.3
39
Gender
Men (%)
57.7
15,077
365
42.3
11,060
365
60.1
833
25
39.9
552
25
58.7
2594
61
41.3
1823
61
57.9
3477
96
42.1
2532
96
54.7
4657
106
45.3
3863
106
53.2
3648
88
46.8
3207
88
60.6
1009
18
39.4
656
18
58.2
1660
29
41.8
1190
29
69.2
534
9
30.8
238
9
60.5
1322
39
39.5
862
39
No. analyzed
No. of tx arms
Women (%)
No. analyzed
No. of tx arms
Prior antihypertensive
drug use (%)
No. analyzed
58.6
5847
123
53.1
147
6
54.5
953
23
55.7
1183
26
54.8
1779
35
54.3
1707
33
73.5
72
2
66.8
870
14
83.1
276
4
70.2
639
15
No. of tx arms
Comorbidities
Diabetes mellitus (%)
No. analyzed
No. of tx arms
LVH (%)
15.7
793
105
27.4
390
37
0.0
0
6
37.5
21
3
8.2
15.4
245
33
32.7
134
12
16.6
187
31
29.4
127
9
18.9
146
25
58.2
92
6
11.5
41
6
12.8
35
3
13.6
83
4
20.3
48
2
100.0
39
2
37.5
6
32.2
156
11
50.0
20
3
83
18
14.5
34
7
No. analyzed
No. of tx arms
1
Duration of tx (wks)
Mean
Range
b
b
14.3
1.4–104
19.8
6–92
17.3
4–104
15.1
13
12.0
15.0
8.9
1.4–104 1.5–104
4–92
4–52
1.4–52
BB = ␤-blocker; ACE = angiotensin-converting enzyme inhibitor; DHP = dihydropyridine; ARB = angiotensin receptor blocker; AAB = ␣-
adrenergic blocker; tx = treatment; LVH = left ventricular hypertrophy.
aNumbers of groups randomized and analyzed for safety are not identical in some drug classes due to incomplete reporting of these numbers in
the original studies.
bNot calculated.
AE, but not the AE as definitely related to a drug.
Also, some authors did not clearly distinguish
between numbers of events and numbers of
patients experiencing those events. These were
all captured as AEs and, whereas for purposes of
this analysis it is assumed these are patients, we
know this is not always the case. Last, regarding
DAEs, sometimes a patient had more than one
AE (e.g., headache and fatigue) leading to
discontinuation, but only one (the first or most
serious one mentioned) was captured. All AEs
and DAEs were categorized according to the
World Health Organization Adverse Reaction
Dictionary (WHOARD).
narrow, extending from diuretics at 39.3% to ␤-
blockers at 32.3%. Placebo AE frequency at
37.3% is a useful context in which to consider
the other agents. Regarding AEs, the frequency
ranking of antihypertensive agents varies by
organ system (Table 2). Rankings of agents for
AEs by organ system do not parallel frequency
rankings of DAEs for the same organ system, as
further described below.
Regarding AEs for the whole body, calcium
channel blockers rank as most frequent (13.2%);
edema was the most frequently reported event.
For respiratory system AEs, ACE inhibitors have
the highest frequency (12.7%), with cough
predominating. For cardiovascular events,
calcium channel blockers rank highest (11.9%),
consisting mostly of flushing and/or vasodilation.
For dermatologic AEs, calcium channel blockers
Adverse Events
The range of total AE frequency among
different classes of antihypertensive agents is

944
PHARMACOTHERAPY Volume 21, Number 8, 2001
Table 2. Type of Antihypertensive Drug and Adverse Events by Organ System
No. of Patients Analyzed (% of patients with this event)
Organ System
Whole body
Event
Total AEs
Total DAEs
Diuretics
1081 (10.0) 3349 (9.2)
702 (0.4)
BB
ACE
3938 (5.6)
2268 (1.0)
CCB
6883 (13.2) 1438 (6.1) 624 (7.1) 1425 (6.8)
3775 (2.2) 863 (0.2) 114 (0.9) 908 (0.6)
2182 (7.3) 537 (4.7) 1030 (5.7)
1003 (0.2) 85 (1.2) 537 (0.4)
660 (1.2) 476 (10.5) 1058 (3.2)
ARB
AAB
Placebo
1746 (1.7)
Respiratory
Total AEs
Total DAEs
978 (7.5)
353 (0.3)
2519 (6.0)
761 (0.4)
4683 (12.7) 1764 (7.8)
3181 (2.0)
1038 (0)
Cardiovascular Total AEs
Total DAEs
867 (1.3)
413 (1.0)
2486 (4.1)
994 (0.8)
2411 (4.1)
1721 (8.5)
5347 (11.9)
2723 (1.3)
298 (0.7)
236 (0.4) 252 (1.2)
616 (0.3) NR
212 (11.8) 47 (8.5)
212 (0) NR
99 (6.1)
593 (1.2)
Dermatologic
Total AEs
Total DAEs
234 (3.8)
49 (2.0)
1017 (4.1)
669 (0.6)
2108 (3.5)
1196 (0.5)
1583 (6.8)
990 (0.8)
189 (2.6)
220 (0.5)
Metabolic
Total AEs
Total DAEs
286 (12.6)
295 (0.3)
264 (0)
43 (0)
862 (3.2)
397 (0.5)
230 (0.9)
265 (0.4)
287 (2.4)
242 (0.8)
Neurologic
Psychiatric
Total AEs
Total DAEs
1106 (16.9) 2991 (11.0) 4092 (10.7) 6502 (17.6) 1888 (9.9) 839 (19.9) 1701 (11.8)
512 (1.8)
1175 (1.3)
2653 (1.5)
3645 (2.3)
1252 (0.8)
257 (1.6) 159 (6.9)
212 (0.5) 47 (0)
1476 (4.1) 500 (6.4)
539 (0.6) 69 (1.4)
89 (1.1) 1230 (1.5)
Total AEs
Total DAEs
296 (3.7)
352 (0.3)
2125 (4.9)
832 (4.3)
1342 (4.7)
1050 (3.0)
1437 (3.4)
884 (0.7)
346 (3.5)
231 (0.4)
Gastrointestinal Total AEs
Total DAEs
828 (5.6)
511 (1.6)
2068 (8.9)
1177 (0.6)
2509 (5.1)
2184 (1.1)
4337 (5.9)
1915 (0.6)
862 (5.0)
318 (0.3)
BB = ␤-blocker; ACE = angiotensin-converting enzyme inhibitor; CCB = calcium channel blocker; ARB = angiotensin receptor blocker; AAB =
␣-adrenergic blocker; NR = not reported.
have the highest frequency (6.8%), whereas for
metabolic AEs, diuretics rank highest (12.6%).
For neurologic AEs, ␣-adrenergic blockers rank
highest in frequency (19.9%), with headache
predominating, followed by dizziness. ␣-
Adrenergic blockers also have the highest
frequency of AEs for psychiatric events (6.9%),
followed by ␤-blockers (4.9%) and ACE
inhibitors (4.7%). Insomnia and sexual
dysfunction were the two most often reported
AEs in this body system. For gastrointestinal
AEs, ␤-blockers rank highest in frequency
(8.9%), with diarrhea noted most often.
frequency in dihydropyridine (DHP) groups was
6.9% and in non-DHP groups, 5.7%. Lowest
frequency of DAEs was seen with diuretics and
angiotensin receptor blockers, each only 3.1%, or
28% lower than placebo. It is noteworthy that
when risk differences relative to placebo are
meta-analyzed for within-study event rates, the
advantage of both diuretics and angiotensin
receptor blockers relative to within-study placebo
groups is statistically significant in both cases
(p=0.038).
Table 2 lists the DAEs by major organ system.
For the WHOARD system of body as a whole
(i.e., systemic or constitutional signs and
symptoms), calcium channel blockers have the
highest frequency of DAEs (2.2%), followed by
␤-blockers (1.7%), ACE inhibitors (1.0%), and
␣-adrenergic blockers (0.9%), all with a
frequency higher than placebo (0.6%). For both
respiratory and cardiovascular DAEs, the ACE
inhibitors rank highest (2.0% and 8.5%,
respectively), followed by ␣-adrenergic blockers
in both instances (1.2% and 6.1%, respectively).
For gastrointestinal DAEs, diuretics were
reported as having highest frequency of DAEs
(1.6%), but all agents studied had a higher
frequency than placebo groups (0.3%). For
neurologic DAEs, calcium channel blockers rank
highest (2.3%), followed by diuretics (1.8%),
both higher than placebo frequency rates (1.5%).
For psychiatric DAEs, ␤-blockers rank highest
Discontinuations due to Adverse Events
Frequency of total discontinuations ranged
from 6.8–17.0% (Table 3); DAE frequencies were
much lower. Frequency of DAEs for placebo
groups (4.3%) serves as a useful benchmark for
interpreting active drug DAE results. Highest
frequency was seen with calcium channel
blockers (6.7%) and ␣-adrenergic blockers
(6.0%), which were 56% and 40% higher,
respectively, than the placebo group DAE
frequency. However, same-study placebo
comparisons could be meta-analyzed only for
calcium channel blocker groups, and here, DAE
event rate was not significantly different (p=0.58)
from the placebo rate, as indicated by risk
difference data for DAEs also presented in Table
3. Within calcium channel blocker groups, DAE

DISCONTINUATION OF ANTIHYPERTENSIVE DRUGS DUE TO ADVERSE EVENTS Ross et al 945
Table 3. Safety Outcomes
Type of Antihypertensive Drug
Calcium Channel Blocker
Diuretics
BB
ACE
Total
DHP
non-DHP
ARB
AAB
Placebo
% of patients with
adverse events
No. analyzed
39.3
694
32.3
2164
36.1
3869
34.3
4418
34.4
3865
34.0
553
38.8
1614
36.1
820
37.3
948
% of discontinuations
No. analyzed
12.7
1628
11.6
3759
10.5
5411
15.3
6441
14.2
4756
17.2
1409
6.8
2044
17.0
1103
11.7
1717
% of DAEs
3.1
4.5
4.7
6.7
6.9
5.7
3.1
6.0
4.3
No. analyzed
1799
4386
6531
9253
7485
1768
2994
1103
2132
% of DAEs in studies
≤ 1 mo
No. of pts with event
No. analyzed
NR
3.2
9
285
1.8
12
650
3.0
27
896
2.9
24
818
3.8
3
78
3.3
2
60
5.6
6
107
1.9
5
259
% of DAEs in studies
> 1 mo
No. of pts with event
No. analyzed
3.0
55
1814
4.5
187
4143
5.1
297
5870
7.1
589
8354
7.5
498
6660
5.4
91
1694
3.1
90
2937
5.9
60
1013
4.5
87
1929
DAEs risk differencea
95% CI
0.027
(0.001,
0.053)
0.038
5
0.018
(-0.008,
0.044)
0.171
6
0.014
(-0.002,
0.029)
0.085
17
-0.005
(-0.022,
0.012)
0.577
14
NC
NC
0.02
(0.001,
0.038)
0.038
7
NC
NC
p value
No. of studies
BB = ␤-blocker; ACE = angiotensin-converting enzyme inhibitor; DHP = dihydropyridine; ARB = angiotensin receptor blocker; AAB = ␣-
adrenergic blocker; No. analyzed = total number of patients evaluated for safety in each outcome category; NR = not reported; ; NC = not
calculated.
aResults of random effects model in placebo comparisons.
(4.3%), followed by ACE inhibitors (3.0%),
calcium channel blockers (0.7%), and
angiotensin receptor blockers (0.5%), all
exceeding the placebo frequency (0.4%). For
dermatologic DAEs, diuretics (2.0%) and calcium
channel blockers (0.8%) ranked higher than
placebo (0.5%). For the frequency of metabolic
DAEs, placebo ranked higher (0.8%) than all
active drugs.
The differences in DAE rates across drug
classes do not appear to be explained by
differences in average study duration. To
determine whether frequency of DAEs differed in
short- vs long-term studies, we stratified the
groups by study duration of 1 month or less
versus more than 1 month. These results show
interesting differences by drug class. In ACE
inhibitor, calcium channel blocker, and placebo
groups, frequency of DAEs more than doubled
from short- to long-term studies, suggesting that
not all DAEs with these drugs occur in the first
month. If all DAEs occurred early, DAE rates
would not differ between short- and long-term
studies. Such comparability of DAE rates is the
case, however, in ␤-blocker, angiotensin receptor
blocker, and ␣-adrenergic blocker groups, where
little difference in DAE frequency is seen between
short- and long-term studies.
Last, we could not relate DAEs to dosage of
drugs since actual dosages at the time of DAE
were not typically reported. However, overall
DAE frequency was 4.0% (226/5655) in fixed-
dosage studies and 5.4% (1108/20,380) in
dosage-titration studies.
Meta-analyses
Within-study risk differences in frequency of
DAEs were also meta-analyzed when at least
three studies were available that contained
similar drug class comparisons (e.g., studies
comparing ␤-blocker vs placebo, or ␤-blocker vs
a common active drug, such as a calcium channel
blocker).
Results of meta-analyses of risk differences of
DAE frequency in placebo-controlled monotherapy
trials support, in general, frequency rankings of
the DAE frequency computed by class of
antihypertensive agent in treatment groups. Tests
for heterogeneity were not significant in any
instance for these meta-analyses. Figure 1
summarizes the meta-analytic estimates of risk
differences and 95% confidence intervals (CIs)

946
PHARMACOTHERAPY Volume 21, Number 8, 2001
for sets of placebo-controlled monotherapy
studies with sufficient data for meta-analysis.
The risk of DAEs was greater in placebo groups
than for same-study ␤-blocker, ACE inhibitor,
diuretic, or angiotensin receptor blocker groups,
the latter two of which reached statistical
significance. Conversely, in placebo-controlled
calcium channel blocker studies, the risk of DAE
was higher for a calcium channel blocker than
placebo but was not significant.
Eleven studies had sufficient numbers of trials
with common active comparisons to submit for
meta-analysis of risk differences for DAEs (Figure
2). Four comparisons reach statistical
significance: diuretic versus calcium channel
blocker, ␤-blocker versus calcium channel
blocker, angiotensin receptor blocker versus ACE
inhibitor, and ACE inhibitor versus ␣-adrenergic
blocker. In each case, the latter of the two drug
classes listed had significantly higher frequency
of DAEs than the former.
for Europe, United States, and the rest of the
world), year of study (since international
standards of DAE reporting according to good
clinical practice have been more widely adopted
in recent years), and quality score (since higher-
quality studies may be more completely reported
and therefore show higher frequency of DAEs
and AEs). Also of interest was whether
frequency of DAEs is different in older patients,
(using 50 yrs of age as the cutoff point), in
women, in groups containing patients with
diabetes, and in groups containing patients with
LVH. Only LVH was significant in the model
containing all covariates, but when studied in a
univariate model, significance was not present.
This is probably due to the different set of studies
with information available for the univariate
model (i.e., included studies had to report only
LVH) as opposed to the multivariate model,
whereby all studies had to report all covariates to
be included in the model.
Sensitivity Analyses
Discussion
We used an analysis of variance procedure to
study the impact of covariates on DAE frequency.
Covariates of interest were geographic location of
study (since DAE reporting practices may differ
The literature, when reviewed systematically
and quantitatively, suggests that frequency of
DAEs with single-agent antihypertensive drugs in
patients with essential hypertension varies across
Drug A vs. Drug B
ACE vs. AAB
#Studies
3
Treatment vs. Control
ARB vs. Placebo
#Studies
7
11
4
ARB vs. ACE
CCB vs. AAB
BB vs. ACE
BB vs. AAB
BB vs. ACE
30
5
14
17
CCB vs. Placebo
ACE vs. Placebo
19
18
12
BB vs. CCB
Diuretic vs. ACE
Diuretic vs. ARB
Diuretic vs. CCB
Diuretic vs. BB
6
5
BB vs. Placebo
3
8
6
Diurectic vs. Placebo
-0.25
-0.20
-0.15
-0.10
-0.05
0.00
0.05
0.10
0.15
0.20
0.25
-0.10
-0.08
-0.06
-0.04
-0.02
0.00
0.02
0.04
0.06
0.08
0.10
*Favors Control
*Favors Treatment
*Favors Drug A
*Favors Drug B
Figure 2. Meta-analysis of risk difference and 95% CI of
DAEs in active controlled trials (DerSimonian and Laird
random effects model7). ACE = angiotensin-converting
enzyme inhibitor; AAB = ␣-adrenergic blocker; CCB =
calcium channel blocker; BB = ␤-blocker; *Favors means
that likelihood of DAEs with this treatment is less than the
comparator.
Figure 1. Meta-analysis of risk difference and 95% CI of
DAEs in placebo-controlled trials (DerSimonian and Laird
random effects model7). ARB = angiotensin receptor
blocker; CCB = calcium channel blocker; ACE =
angiotensin-converting enzyme inhibitor; BB = ␤-blocker;
*Favors means that likelihood of DAEs with this treatment
is less than the comparator.

DISCONTINUATION OF ANTIHYPERTENSIVE DRUGS DUE TO ADVERSE EVENTS Ross et al 947
DAE frequency may be higher10 because some
patients have more comorbid conditions and
receive more concomitant drugs than others.
Choosing drugs for patients with comorbid
conditions requires knowledge of toxic responses
of different organ systems caused by different
drugs. We recognize that many patients with
hypertension require two or more antihypertensive
agents. The full nature and extent of drug
interactions are not known with regard to DAEs,
so we should not extrapolate these results to
patients receiving many drugs.
drug classes by a factor of two, from lowest
frequency in diuretic groups to highest in
calcium channel blocker groups. Differences
across drug classes, however, were not
statistically significant in most instances. We
know this from indirect comparisons9 facilitated
by the meta-analyses of studies with a common
comparator (i.e., placebo), as summarized in
Figure 1, where it is evident that the confidence
intervals overlap. Furthermore, the placebo DAE
frequency observed in these trials is of interest
for contextual purposes in which to evaluate
DAE frequency for active drugs. The meta-
analyses suggest that only calcium channel
blocker groups had higher frequency, although
not significant, of DAEs relative to same-study
placebo groups; diuretics and angiotensin
receptor blockers had significantly lower
frequency.
Conclusion
Data are greatly needed to support consider-
ations of drug toxicity and impact on quality of
life in selection of drug therapy, especially for
chronic asymptomatic conditions such as
hypertension. Recognizing the limitations of
current literature, we believe this review provides
the best available evidence on the frequency of
DAEs in patients with essential hypertension who
are otherwise well and are receiving single-agent
antihypertensive therapy.
Meta-analyses of active comparison trials
suggest that calcium channel blockers are more
likely to be associated with DAEs than diuretics
or ␤-blockers, and that ACE inhibitors are more
likely to be associated with DAEs than
angiotensin receptor blockers.
The DAE frequency results in the analyses
stratified by study duration suggest the intriguing
possibility that if a DAE is going to occur, it
probably will occur in the first month in patients
receiving ␤-blockers, angiotensin receptor
blockers, and ␣-adrenergic blockers but may be
delayed past the first month in patients receiving
ACE inhibitors or calcium channel blockers.
All of these results should be considered in
light of strengths and limitations of source
material and review methods. One strength of
this review is the use of comprehensive computer
and manual search to identify all relevant
published clinical trials. This search most likely
did not miss any relevant published data.
Furthermore, the chance for bias or error in
extraction of data was reduced by using two
reviewers to achieve consensus on all extracted
data. A major limitation was the heterogeneity of
rules used by investigators for reporting AEs.
Different frequency thresholds and/or
relationships to study drug introduce uncertainty
to the estimates of event rates. Discontinuations
due to adverse events were reported much more
clearly than AEs, but the lack of reporting of
actual timing of DAEs relative to drug initiation
is a limitation.
Acknowledgment
We thank Dr. William B. White for reviewing the
manuscript and providing valuable comments.
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